Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart.
OBJECTIVE
Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, can be delivered to targeted tissues by means of a replication-deficient adenovirus (Ad) vector. We hypothesized that direct administration of Ad vector expressing the VEGF121 complementary deoxyribonucleic acid (AdGVVEGF121.10) into regions of ischemic myocardium would enhance collateral vessel formation and improve regional perfusion and function.


METHODS
Yorkshire swine underwent thoracotomy and placement of an Ameroid constrictor (Research Instruments & MFG, Corvallis, Ore.) on the circumflex coronary artery. Three weeks later, myocardial perfusion and function were assessed by single photon emission computed tomography imaging (SPECT) with 99mTc-labeled sestamibi and by echocardiography during rest and stress. AdGVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10(8) pfu/site). Four weeks later, these studies were repeated and ex vivo angiography was performed.


RESULTS
SPECT imaging 4 weeks after vector administration demonstrated significant reduction in the ischemic area at stress in AdGVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in AdGVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with AdGVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in AdGVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in AdGVVEGF121.10 animals.


CONCLUSIONS
An Ad vector expressing the VEGF121 cDNA induces collateral vessel development in ischemic myocardium and results in significant improvement in both myocardial perfusion and function. Such a strategy may be useful in patients with ischemic heart disease in whom complete revascularization is not possible.
Mack
C A
CA
Department of Cardiothoracic Surgery, New York Hospital-Cornell Medical Center, New York 10021, USA.
Patel
S R
SR
Schwarz
E A
EA
Zanzonico
P
P
Hahn
R T
RT
Ilercil
A
A
Devereux
R B
RB
Goldsmith
S J
SJ
Christian
T F
TF
Sanborn
T A
TA
Kovesdi
I
I
Hackett
N
N
Isom
O W
OW
Crystal
R G
RG
Rosengart
T K
TK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018076:DNA, Complementary / Q000627:therapeutic use*; D004452:Echocardiography; D016228:Endothelial Growth Factors / Q000627:therapeutic use*; D005080:Exercise Test; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008222:Lymphokines / Q000627:therapeutic use*; D009200:Myocardial Contraction / Q000502:physiology; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019275:Radiopharmaceuticals; D013552:Swine; D017256:Technetium Tc 99m Sestamibi; D015899:Tomography, Emission-Computed, Single-Photon; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019275:Radiopharmaceuticals; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017256:Technetium Tc 99m Sestamibi